The challenge of explaining natural host resistance to HIV-1 infection (individuals who remain uninfected despite extensive sexual exposure to the virus) remains incompletely addressed. While some host genetic variants that influence natural resistance to HIV-1 infection have been identified few such studies have been conducted in cohorts of Africans (who are most impacted by this pandemic), and no comprehensive genome-wide evaluation that captures common and low-frequency host genetic variation influencing HIV-1 infection has been done in any population. One reason for this is that such studies must control for epidemiologic factors (e.g., level of plasma HIV-1 in the infected parter, and male circumcision status in the uninfected partner) that modify HIV-1 exposure risk. These exposure data must be collected from both the HIV-1 infected and HIV-1 uninfected sexual partner necessitating recruitment of HIV-1 serodiscordant couples (one partner HIV-1 infected and the other uninfected) - a costly and complex study design. Over the past 6 years, in the course of conducting 2 HIV-1 prevention clinical trials and an observational study, we have recruited 3 large cohorts of African HIV-1 serodiscordant heterosexual couples encompassing nearly 8,600 couples (17,200 individuals) each with 12 to 36 months of monthly or quarterly follow-up to evaluate for HIV-1 seroconversion in the initially HIV-1 uninfected partner. The central specimen repository for these cohorts is located at the University of Washington and currently holds over a million aliquots of a wide range of clinical sample types including whole blood for genomic studies. Epidemiologic, clinical and behavioral data have also been collected from all participants permitting detailed evaluation of HIV- 1 exposure factors affecting risk of HIV-1 transmission. Here we propose to use this unique existing specimen and data repository and next generation DNA sequencing technology to perform a comprehensive analysis for host genomic factors affecting HIV-1 transmission. In order to broadly capture host genetic risk factors, we propose to completely sequence the genomes of 50 individuals who became HIV-1 infected with low levels of HIV-1 exposure and 50 individuals resistant to HIV-1 infection despite high levels of heterosexual exposure to the virus. This extreme phenotype approach will maximize our power to capture host genetic factors associated with HIV-1 transmission. A set of high priority variants identified from these sequence data will then be genotyped in the remaining cohort to identify host genetic variants in Africans associated with natural host susceptibility and resistance to HIV-1 transmission. These data could provide critical insights particularly toward developing HIV-1 prevention interventions (e.g. vaccine adjuvants or gene expression modulators) to broadly elicit host resistance to HIV-1 infection.